The present invention relates to processes for preparing erythromycin derivatives and to intermediates thereof, and particularly relates to a process for preparing 6-O-substituted ketolide derivatives starting from erythromycin and to intermediates thereof.
Macrolide antibiotics including erythromycin A have a strong antibacterial activity against Gram-positive bacteria, some Gram-negative bacteria, Mycoplasmas and the like, and have been widely used as agents for the treatment of infections caused by these bacteria. Furthermore, many erythromycin derivatives have been synthesized for the purpose of the improvement of pharmacokinetic properties of erythromycin A, and some of them have already been clinically used as excellent antibiotics. For example, clarithromycin (6-O-methylerythromycin A, U.S. Pat. No. 4,331,803) has been widely used as a therapeutic agent of respiratory tract infections due to its excellent biological properties. There has been recently reported the derivatives which are generically called ketolides and have a potent antibacterial activity against macrolide-resistant bacteria. The structural features of these derivatives are such that the cladinose group at the 3-position of erythromycin A has been removed, and converted into a carbonyl group, the hydroxyl group at the 6-position has been alkylated, and the hydroxyl groups at the 11- and 12-postions have been converted into a cyclic carbamate. Among these ketolides, there is 3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminyl erythronolide A 11,12-cyclic carbamate (U.S. Pat. No. 5,866,549, and J. Medicinal Chemistry, vol. 43, pp.1045-1049 (2000)), which has a strong antibacterial activity against both of macrolide-sensitive and macrolide-resistant bacteria that cause respiratory tract infections. As mentioned above, this compound is prepared by modifying at three positions, i.e., at the 6-, 3- and 11,12-positions. The preparation process reported is carried out by once converting the carbonyl group at the 9-position into an oxime derivative, modifying at the 6-position and reproducing a carbonyl group at the 9-position, therefore this manufacturing process needs many steps, and is complicated.
Problems to be Solved by the Invention
An object of the present invention is to provide processes for preparing erythromycin derivatives and intermediates thereof, and more particularly to provide preparation processes useful for an efficient synthesis of a 6-O-substituted ketolide derivative.
Means for Solving the Problems
As a result of diligently studies, the present inventors have found a process for leading to a 6-O-substituted ketolide derivatives, which comprises combining a characterized step of introduction of a substituent at the 6-position by selective cleavage of the Cxe2x80x94O bond of the cyclic acetal at the 9-position side via a 6,9-cyclic acetal 5-O-desosaminyl erythronolide derivative, a step of conversion into carbonyl groups at the 9- and 3-positions, and a step of 11,12-cyclic carbamation, thereby the present invention have been accomplished. Specifically, this process is useful as a process for the synthesis of 3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminyl erythronolide A 11,12-cyclic carbamate which has been recently reported to have a potent antibacterial activity, and the like.
That is, the present invention is directed to a process for preparing Compound (V) defined below, which comprises the steps of:
(A) providing Compound (I) of the formula: 
wherein R1 and R2, which may be the same or different, are a hydrogen atom, formula xe2x80x94COxe2x80x94RA wherein RA is a C1-3 alkyl group, C1-3 alkyl group substituted with 1-3 halogen atoms, C1-3 alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3 atoms/substituents selected from the group consisting of C1-3 alkyl group, C1-3 alkoxy group, nitro group, cyano group, halogen atom, acetyl group, phenyl group and hydroxy group, or a silyl group substituted with 2-3 substituents selected from the group consisting of C1-4 alkyl group, phenyl group and benzyl group,
by reaction of erythromycin with ethylene carbonate, subsequent reduction of ketone in 9-position, and optional protection of hydroxy groups in 2xe2x80x2- and/or 4xe2x80x3-positions,
(B) reacting Compound (I) with a compound of the formula: 
wherein A is CHxe2x95x90CH or Cxe2x89xa1C; R5 and R6, which may be the same or different, are a C1-7 alkyl group,
and optionally protecting a resulting 3-hydroxy group, to obtain Compound (II) of the formula: 
wherein R3 is the same as R1 defined above; R2 and A are as defined above,
(C) reacting Compound (II) with a compound of the formula:
Xxe2x80x94R4xe2x80x83xe2x80x83(2) 
wherein X is a halogen atom; R4 is the formula: 
wherein R7 and R8 are a hydrogen atom or, alternatively, they form a benzene nucleus together with adjacent carbon atoms, or the formula: 
wherein Ar is a pyridyl group, quinolyl group or aryl group,
to obtain Compound (III) of the formula: 
wherein A, R2, R3 and R4 are as defined above,
(D) reacting Compound (III) with a compound of the formula: 
wherein R9 is a hydrogen atom, chlorine atom, linear or branched C1-4 alkyl group, C1-3 alkoxy group, phenyl or benzyl group; R10 and R11, which may be the same or different, are a chlorine atom, linear or branched C1-4 alkyl group, C1-3 alkoxy group, phenyl group or benzyl group,
to obtain Compound (IV) of the formula: 
wherein A, R2, R3 and R4 are as defined above, and
(E) subjecting Compound (IV) to carbonylation at 9-position, carboxylation at 3-position, 11,12-cyclic carbamation and deprotection of 2xe2x80x2-hydroxy group, to obtain Compound (V) of the formula: 
wherein A and R4 are as defined above.
The present invention is illustrated in more detail as follows.
In the present invention, the term xe2x80x9cC1-7 alkyl groupxe2x80x9d refers to linear or branched alkyl groups, which include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group and heptyl group. The term xe2x80x9cC1-3 alkoxy groupxe2x80x9d refers to methoxy, ethoxy and propoxy groups. The term xe2x80x9chalogen atomxe2x80x9d refers to fluorine, chlorine, bromine, iodine atom and the like.
The present invention relates to a process for preparing Compound (V) from erythromycin A as a starting material, for example, according to the following reaction scheme, and to intermediates thereof. 
wherein A and R1 through R4 are as defined above, and more particularly, A is CHxe2x95x90CH or Cxe2x89xa1C, R1 is hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group or a triethylsilyl group, R2 is hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group or a t-butyldimethylsilyl group, R3 is hydrogen atom, an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group or a triethylsilyl group, and R4 is a pyridyl group, a quinolyl group, a pyridylthienyl group or a pyridylimidazolyl group.
Step 1. Compound (I) can be prepared according to a method described in WO9813373. That is, erythromycin A is reacted with ethylene carbonate in the presence of a base in an inert solvent to give an erythromycin A 11,12-cyclic carbonate compound. Here, the inert solvent includes diethyl ether, ethyl acetate, dichloromethane, chloroform, acetone, N,N-dimethylformamide, toluene, tetrahydrofuran and a mixture thereof. The base includes sodium carbonate, potassium carbonate, cesium carbonate and pyridine. Next, the carbonyl group at the 9-position is reduced into a hydroxyl group by a reducing agent in an organic solvent, thereby 9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate can be obtained. The organic solvent used herein includes methanol, ethanol, isopropanol, propanol, tetrahydrofuran and N,N-dimethylformamide. The reducing agent includes lithium borohydride, potassium borohydride, sodium cyanoborohydride and sodium borohydride. The hydroxyl group at the 2xe2x80x2-position is then protected with an acetyl, propionyl, benzoyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl group or the like to obtain Compound (I). In order to accelerate the reaction, a base can be added for the acylation, and a salt with an acid can be added for the silylation. Examples of the base to be used are N,N-dimethylaminopyridine, pyridine, triethylamine, imidazole, sodium bicarbonate and potassium carbonate. Examples of the salt with an acid to be used are pyridine hydrochloride and ammonium chloride.
Step 2. Compound (I) obtained in Step 1 can be heated together with a compound of the formula: 
wherein R5 and R6 are as defined above, in an inert solvent in the presence of an acidic catalyst to obtain a decladinosylated 6,9-cyclic acetal compound (II). Here, the inert solvent includes dichloromethane, chloroform, dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, etc. The acidic catalyst to be used includes pyridinium p-toluenesulfonate, pyridine hydrochloride, 3-pyridinesulfonic acid, trimethylamine hydrochloride, triethylamine hydrochloride, etc, and is preferably, pyridinium p-toluenesulfonate. Examples of the compound of formula (1) to be used are acrolein dimethyl acetal, acrolein diethyl acetal, acrolein di-n-propyl acetal, acrolein diisopropyl acetal, acrolein di-n-butyl acetal, acrolein diisobutyl acetal, propiolaldehyde dimethyl acetal, propiolaldehyde diethyl acetal, propiolaldehyde di-n-propyl acetal, propiolaldehyde diisopropyl acetal, propiolaldehyde di-n-butyl acetal, propiolaldehyde diisobutyl acetal, etc.
Step 3. Compound (II) obtained in Step 2 can be reacted with a compound of the formula: 
in which R7, R8 and X are as defined above, or a compound of the formula: 
in which Ar and X are as defined above, in an inert solvent in the presence of, for example, a palladium catalyst to obtain Compound (III). In this case, copper iodide and phosphine may be optionally added. The inert solvent includes toluene, tetrahydrofuran, dioxane, dimethoxyethane and N,N-dimethylformamide, and preferably toluene, tetrahydrofuran and N,N-dimethylformamide. The compound of formula (2) includes quinolyl chloride, pyridyl chloride, quinolyl bromide and pyridyl bromide and the compound of formula (3) includes pyridylthienyl chloride and pyridylthienyl bromide, and of these compounds, quinolyl bromide, pyridyl bromide and pyridylthienyl bromide are preferable.
Step 4. Compound (III) can be reacted with a compound of the formula: 
wherein R9, R10 and R11 are as defined above, in an organic solvent in the presence of an activating agent such as a Lewis acid to obtain Compound (IV). Here, the organic solvent includes nitrobenzene, nitrotoluene, trichlorotoluene, benzonitrile and methylbenzoate, and preferably nitrobenzene and nitrotoluene. Here, the compound of formula (6) includes trimethylsilane, triethylsilane, trichlorosilane, phenyldimethylsilane, diphenylsilane, triphenylsilane, triethoxysilane, diethylsilane and t-butyldimethylsilane, and preferably triethylsilane and t-butyldimethylsilane. The activating agent to be used includes a Lewis acid (e.g., titanium tetrachloride, aluminum chloride, zirconium tetrachloride, tin tetrachloride, ferric trichloride, zinc chloride and trifluoroboran etherate), trifluoromethane sulfonate and Nafion (registered trademark), and preferably titanium tetrachloride.
Step 5. Compound (IV) wherein R3 is a hydrogen atom can be subjected to a reaction using a sulfur compound such as dimethyl sulfoxide (DMSO) and dimethyl sulfide (Me2S) and an activating agent such as acetic anhydride (Ac2O), N-chlorosuccinimide (NCS) or oxalyl chloride, whereby the hydroxy groups at the 3- and 9-positions are simultaneously oxidized to form a 3,9-dioxo compound, which is then led to 12-O-imidazolyl carbonyl compound using N,Nxe2x80x2-carbonyldiimidazole and a base. Subsequently, ammonolysis using ammonia gas and intramolecular Michael addition reaction can lead to a 11,12-cyclic carbamate compound to obtain Compound (V). In this case, a base can also be added in order to accelerate the intramolecular Michael addition reaction. Here, the base includes DBU, DBN, LiH, NaH, KH, NaHMDS, Cs2CO3, K2CO3, imidazole, KO-t-Bu or a mixture thereof. Compound (IV) wherein R3 is protected is subjected to oxidation at the 9-position in the same manner as in the above oxidation step, 11,12-cyclic carbamation, deprotection of the hydroxyl group at the 3-position, and then oxidation at the deprotected 3-position in the same manner as described above to obtain Compound (V).